The nervous system achieves stability by regulating the strength of connections between neurons to preserve activity within a narrow range. This 'synaptic homeostasis' is thought to be critical for the normal function of the nervous system, and disruption of this process may underlie neurological disorders such as epilepsy and addiction. Synaptic homeostasis is a robust phenomenon that is preserved from invertebrates to mammals, yet the molecular mechanisms involved are not well understood. To investigate the molecules involved in synaptic homeostasis, we propose to use the larval neuromuscular junction (NMJ) of Drosophila melanogaster as a model system. The NMJ exhibits robust synaptic homeostasis when challenged with genetic or pharmacological manipulations that alter excitability of the muscle. The formidable genetics of Drosophila allows for rapid and inexpensive screening of candidate molecular pathways. Furthermore, the highly stereotyped connectivity between nerve and muscle allows for highly reproducible electrophysiological and imaging experiments that assay synaptic function. This research aims to investigate the role of a candidate molecular pathway that is highly conserved from fly to mammal. Preliminary studies have implicated the cyclin dependent kinase 5 (Cdk5) in the homeostatic regulation of synaptic strength. Interestingly, several recent studies from mammalian systems point to a role for Cdk5 in regulating synaptic release, however, the molecular pathways and mechanisms involved are unknown. The following experiments are designed to address the how Cdk5 interacts with molecules at the synapse to regulate synaptic strength. PUBLIC HEALTH RELEVANCE: The research outlined in this application will use the powerful genetics of Drosophila to provide a greater understanding of how mutations in highly conserved genes disrupt normal brain function. Insights from this research will further our understanding of the genetic basis of neurological disorders such as epilepsy, addiction, and schizophrenia.